5alpha, 6beta-dichloro-16, 17-epoxy-allopregnane-3beta-ol-20-one and esters thereof



United States Patent 3,136,759 a,Efl-DIEHLORO-16,17-EPOXY-ALLOPREGNANE-3,6-OL-2tl-ONE AND EfiTERS THEREOF Percy L. Julian and John W. Cole, OakPark, Ill., assignors, by mesne assignments, to Chas. Pfizer & (30.,lac,

New York, N.Y., a corporation of Delaware No Drawing. Filed May 17,1954, Ser. No. 430,442 3 Claims. (Cl. 25tl239.55)

This invention relates to a novel process of chlorinating A -steroids.More particularly, it relates to an ima proved process for preparingtrans-5,6-dichlorosteroids,

and especially it relates to the preparation of trans-5,6-

- dichloro-16,l7-epoXy-pregnan-3/3-ol-20-one acetate.

In investigations carried out on steriods, it has long u been known thatnuclear double bonds are susceptible to attack by various reagents.Accordingly, methods were devised to protect such reactive centers ofthe steriod nucleus against undesirable attack. Thus, the 5,6-doublebond present in many steroids can be protected by bromination to formthe 5,6-dibromide which, upon treatment with chromous chloride, zinc andacetic acid and the like, is readily debrominated, regenerating theoriginal double bond. This well-known synthetic procedure is aptlyillustrated by the synthesis of Reichsteins Substance S. In theprocedure devised by Julian et al., J.A.C.S. 72, 5145 (1950), thepracticality of protecting the 5,6- double bond, fortunately present in16-dehydropregnenolone, obtainable from the readily available soyasterols or Mexican sapogenins, has made this procedure commerciallyfeasible. On the other hand, the method devised by Gallagher et al.,J.A.C.S. 71, 3262 (1949), employs as the starting material relativelyrare pregnan-3a-ol-20- one, thus involving the unwelcome task ofintroducing the double bond into ring A of the steroid nucleus.

However, as is well known, bromination of ethylenic double bonds leadsto a mixture of geometric isomeric dibromides, which differ in the easeof and behavior upon debromination. Further, as pointed out originallyby Mauthner, Monatsch. 15, 91 (1894), and studied most recently byBarton, J.A.C.S. 72, 1066 (1950'), 5,6-steroid dibromides, such ascholestene dibromide, undergo mutarotation in solution even at roomtemperature. Inas much as for usual synthetic work it is desirable to obtain (1) pure compounds, or more specifically compounds which aresufiiciently stable for purification and identification, and (2)compounds which can be efficiently handled in a proposed syntheticscheme, it will be seen that the dibromides are objectionable since (1)upon conventional bromination A -steroids form mixtures of 5,6-dibromides, (2) in solution at ordinary temperatures the less stableisomer undergoes a spatial shift to a more stable form, and (3) theisomeric dibromides differ in their behavior towards debrominatingagents. However, as has been shown by Barton, J.A.C.S. 72, 370 (1950),the addition of chlorine in the presence of antimony trichloride to the5,6-double bond of cholesteryl benzoate yields essentially onedichlorocholestan-3B-ol-benzoate, which does not undergo mutarotation.This, according to Barton, is a trans form, i.e., 5a,6B-dichloro-,which, in accordance with the prevailing theory of elimination ofnuclear substituents, should be dechlorinated, and thus to regeneratethe 5,6-double bond, more readily than a cis form. In accordance withthe above theoretical considerations, we have found that the products ofdirect chlorination of A -steroids are stable and readily dechlorinated.Further, such dichlorides are easily purified and give rise to nicelycrystalline products upon further syn- 'thetic processing.

It is accordingly an object of the present invention to rovide a novelprocess for chlorinating A -steroids.

3,136,759 Patented June 9, 1964 A further object is to provide animproved process for producing A -trans-dichloro-steroids.

Another object is to provide a novel. process for producing50:,6fl-diChlOIO-St6f0id5.

Other objects will be apparent to those skilled in the art from thefollowing description.

In the course of our investigations, we have made the further surprisingdiscovery that chlorination of A steroids, in the presence of a basicsubstance rather than acidic salts, such as antimony trichloride, whichwas used by Barton,,enabled us to prepare the trans-dichlorides inexcellent yield.

The process of our invention is broadly applicable to any A -steroid. Ingeneral, we have found it practical to dissolve the A -steroid in anonreactive solvent and to the solution add a basic material such aspyridine. The mixture is cooled to about 0 C. and to it is added aslight excess of chlorine. The chlorine is added slowly until a paleyellow color persists, indicating that the compound will not react witha further amount of chlorine. On small scale runs it is preferred to addthe chlorine in the form of a cold solution thereof in a suitablenonreactive solvent, e.g., carbon tetrachloride. In larger batches it ispreferable, as a matter of convenience, to add the chlorine directlyinto the cooled agitated solution of the A -steroid. Thereafter thereaction mass is washed to remove unreacted chlorine, the basicmaterial, etc. and the solvent is removed, e.g., by distillation withsteam. The product is isolated by filtration and purified byrecrystallization from a suitable solvent.

The amount 'of basic material present is preferably at least suflicientto bind all of the hydrogen chloride produced by anomalous reaction,i.e., random chlorination. In general, we have found that an amount ofbasic material equivalent to about 0.1 part by weight of the A steroidto be sufficient when pyridine is the base used. It will be within theskill of the trained chemist to follow the reaction and should the massbecome acid or fumes of hydrogen chloride emanate from the mixture, toadd more of the basic substance. It is not intended to imply that thebasic material functions only to bind hydrogen chloride and thus toimprove the process. It is believed that the basic material functionsalso to alter the stereospecific course of the reaction, since theproduct is essen tially free of cis-dichlorides. Depending upon thesteroidal material being chlorinated, we obtain from about to of thetrans-dichloride and from 5% to 15% of chlorinated by-products.

The following examples will illustrate the process of our invention:

EXAMPLE 1 A solution of 20 g. of 16,17-epoxy-5-pregnen-3/3-ol-20- oneacetate in cc. of methylene chloride to which 2 cc. of pyridine has beenadded was cooled to and maintained at about 0 C. in an ice-salt mixture.To the agitated mass 4.45 g. of chlorine dissolved in 91 cc. of carbontetrachloride was added dropwise during a period of 8 minutes. Thefaintly yellow mass was agitated for two minutes thereafter. After beingwashed with 2% aqueous hydrochloric acid and with water, the reactionmixture was distilled with steam for ten minutes. The white crystallineslurry was washed and about one-fourth of the liquor was decanted.Methanol, in amount equivalent to about half of the remaining volume,was added and the slurry was filtered. The filter-cake was washed with50% aqueous methanol and dried. The crude product amounted to 23.3 g.,97% of the theoretical amount obtainable, and melted at 206 to 212 C.;optical rotation (a) =18 (CHCIg). Upon recrystallization from acetone,the product, 16,17-epoxy-5a,6,8-dichloro-allopregnan-Sfl-ol-ZO-oneacetate, melted at 218 to 221 C. The

EXAMPLE 2 A solution of 7.48 'g. of 5-pregnene-3B,17wdiol-20-one3-acetate dissolved in 100 cc. of chloroform was cooled in an icebath.After the addition of 0.75 cc. of pyridine,

1.704 g. of chlorine in cc. of carbon tetrachloride were added dropwisein 10 minutes. The faintly yellow solution was washed with water,aqueous sodium bicarbonate and finally with water. The washed solutionwas concentrated under vacuum to a semi-solid mass, taken up inmethylene chloride and boiled for a short time. Then, after the additionof methanol, the major portion of the methylene chloride was taken offunder vacuum. The mass was crystallized by cooling and then filtered. Inthis manner 6.0 g., 67.5% of theory, of5u,6fl-dichloroallopregnane-3B,17ec-diol-20-one 3-acetate, M.P. 222 to225 C., was obtained.

Analysis. Calculated Cl=15.95%. Cl:16.70%.

Repeated recrystallization of a similarly prepared material frommethylene chloride-methanol gave a product having 16.1% chlorine M.P.222 to 228 C.; (a) =-66.4 (CHCl Hydrolysis of the product withmethanolic potassium hydroxide yielded the free -hydroxy derivative,M.P. 199 to 201 C.

Repetition of the above experiment, but without the addition ofpyridine, results in a yield of 57% of the theoretical amount obtainableof a product melting at 216 to 223 C. A strong odor of hydrogen chloridewas noted at the conclusion of the addition of the chlorination,indicating some substitution reaction. This fact, plus the lower yieldand purity of the crude reaction product, is an indication of the valueof the presence of basic substances.

EXAMPLE 3 A solution of 7.12 grams of 5,16-pregnadien-3/3-ol-20- oneacetate in 105 cc. of methylene chloride, containing 2 cc. of pyridine,was cooled to 1 C., and to it was added a solution of 1.68 g. ofchlorine dissolved in 35 cc. of carbon tetrachloride. The chlorinesolution was added dropwise over a period of 3 to 4 minutes. Theresulting mixture was agitated for about five minutes thereafter. It waswashed with aqueous hydrochloric acid and then with water. The washedsolution was dried over anhydrous sodium sulfate and then concentratedto a low volume. The residue was diluted with 50 cc. of methanol andevaporated to incipient crystallization. After being cooled, thecrystals were filtered to recover 0.9 gram of unchanged startingmaterial.

The mother liquor on dilution with 5050 methanolether gave 3.9 g. ofreaction product, 5a,6fi-dichloro-16- allopregnene-3-ol-20-one acetate,which, after recrystallization from dilute acetone, melted at 137 to 141C. UV: E at 239 m,u=9800.

EXAMPLE 4 To a cold, 20 C., solution of 12.5 g. of cholesteryl benzoatedissolved in 150 cc. of chloroform and containing 2.5 cc. of pyridine,2.0 g. of chlorine dissolved in 45 cc. of chloroform was added dropwiseduring three minutes.

The pale yellow solution was extracted with dilute aqueous hydrochloricacid, aqueous sodium bicarbonate and lastly with water. The solventsolution was dried Found over anhydrous sodium sulfate and thenevaporated to dryness under vacuum.

The pale yellow residue was recrystallized from ethyl acetate-methanoland gave 10.36 g. first crop, M.P. 127- 131 C., plus 2.1 g. second crop,M.P. 121-127 C.; 126130 C. after recrystallization, of5a,6fi-(11Chl01'0- cholesteryl benzoate. The combined first and secondcrops represent a yield of 87% of the theoretical amount obtainable.

Analysis for C H O Cl .Percent Cl calculated: 12.66%. Percent Clfound=12.67%.

Rotation (a) =22.6 (chloroform).

EXAMPLE 5 Preparation of 5,6-Dichlor0 (Trans)-Di0sgenin Acetate 45.6 g.of diosgenin acetate was dissolved in 500 cc. CHC13 and cooled to 20 C.in acetone-Dry Ice bath. Ten cc. pyridine was added and then a solutionof 8 g. of chlorine in 180 cc. of chloroform was added dropwise. Thediosgenin solution was dark green colored and no color change was noted.The solution was stirred for about fifteen minutes after chlorineaddition. The solution was washed with water, bisulfite, dilute HCl,aqueous bicarbonate and water, then filtered through Na SQ; andevaporated to dryness in vacuo. The residue was a dark orange tarry oil,which crystallized on standing.

The crude crystallizate was taken up in ethyl acetate, treated withactivated carbon and filtered. The filtrate was concentrated and thendiluted with MeOH, and set aside to crystallize. The resulting slurrywas filtered and washed with 50-50 MeOH-EtOAc: first crop:30.0 g. M.P.217-222 C.

The mother liquor was concentrated to a low volume, diluted with MeOH,seeded and put in cold room overnight to obtain a second crop; secondcrop=6.5 g.

First crop material recrystallized from acetone gave buff-coloredcrystals, M.P. 224-226 C.

Percent chlorine: C H O Cl calc. 13.47%; found 13.46,13.36.

No further attempt was made to isolate material from second crop motherliquor, which was quite tarry. Total yield obtained was by weight, or69% of theory.

The acetoxy-diosgenin-dichloride thus obtained can be treated in thesame manner as diosgenin for the production of the analogous A -pregnenederivative, 5a,6,B-dichloro-16-allopregnene-3fi-ol-20-one acetate,which, in turn, upon treatment with alkaline hydrogen peroxide, yieldsthe epoxy acetate of Example 1.

The free 3-hydroxy compound can also be employed and the esters producedat any stage can be hydrolyzed to produce the analogous free 3-hydroxycompound- It can readily be seen from the above illustrative examplesthat a method of preparing 5,6-transdichloro-steroids of good qualityand in high yields has been provided. It is to be understood, moreover,that our invention is not to be limited to the treatment of theparticular compounds enumerated, but is broadly applicable to thestereospecific dichlorination of A steroids.

Other bases, preferably tertiary amines, can be used, although pyridineand its alkyl derivatives, e.g., picolines, lutidenes, etc., arepreferred. Such other tertiary amines as dimethyl aniline, triethylamine and the like can be used in the process of our invention.

It is preferred to conduct the process of our invention at temperaturesbetween 30 and 10 C., and especially at 0 C. Because of the greatertendency to random chlorination at increased temperatures and thereduced reaction rate at decreased temperatures than that of ourpreferred range, the optimum reaction temperature will be a function ofthe reactivity of the particular A -steroid being chlorinated. Theselection of the optimum temperature for a particular compound will bewithin the range of 30 and than the acetyl can be used. Because of theease of 0b- 10 taining them, the lower alkyl acyl esters are preferred,although others such as the benzoyl, naphthoyl, hemisuccinyl, picolanyland like acyl radicals can be used instead of the illustrated acetylradical.

Our invention has been described in the foregoing 15 specification, ofwhich the illustrative examples are a part. Where recourse has been madeto certain theoretical explanations, it is to be distinctly understoodthat the ultimate correctness of said theories is in noway to be held asa limitation upon our invention.

Having described the invention, what is claimed is:

1. A compound selected from the class consisting of 5a,6}3-dichloro16,17 epoxy-allopregnane-3fi-ol-ZO-one; and the 3 esters thereof with alower hydrocarbon carboxylic acid.

2. 5u,6/3-dich1oro-16,17-epoxy allopregnane-3B-ol-20- one.

3. 5a,6fl-dichloro 16,17 epoxy-allopregnane-3[3-01-20- one acetate.

References Cited in the file of this patent UNITED STATES PATENTS2,232,438 Butenandt Feb. 18, 1941 2,313,732 Butenandt Mar. 16, 19432,340,388 Inhoffen Feb. 1, 1944 2,686,181 Julian Aug. 10, 1954 2,884,417Cutler et a1 Apr. 28, 1959 OTHER REFERENCES Barton: J. American Chem.Soc., pp. 370-374, vol. 72, January 1950.

Julian: J. American Chem. Soc., pp. 5145-5147, November 1950.

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF5A,6B-DICHLORO-16,17 - EPOXY-ALLOPREGANE-3B-OL-20-ONE; AND THE 3 ESTERSTHEREOF WITH A LOWER HYDROCARBON CARBOXYLIC ACID.